Proprotein convertases, also known as prohormone convertases, neuroendocrine convertase, or Proprotein Convertase Subtilisin/Kexin Type (PCSK), are capable of cleaving precursor proteins. The precursor proteins that are known to be cleaved by proprotein convertases include growth factors and hormones, receptors, and bacterial endotoxins. Nakayama, K., Biochem. J. 327: 625-635 (1997). The first proprotein processing protease discovered was Kex2 protease from S. cerevisiae. Rockwell et al., Chem. Rev. 102: 4525-4548 (2002). Kex2 homologues identified in mammalian cells include PC1/3, PC2, PACE4, PC4, PC5/PC6, and PC7. See id.
Each member of the convertase family exhibits a unique tissue distribution; different cell types were found to express individual combinations of these enzymes. PC4 is limited to testicular germ cells. Seidah et al., Mol. Endocrinol. 6(10): 1559 (1992). PC1/3 and PC2 are restricted to endocrine and neuroendocrine tissues. Seidah et al., NIDA Res. Monogr. 126:132 (1992). PACE 4 and PC5 are expressed in several tissues, while PC7 exhibits an even more common tissue distribution. Furin is expressed ubiquitously.
The cellular sublocalisation of the endoproteases is an important determinant for their physiological function, PC1/3, PC2, and PC5A, an isoform of PC5/6, are involved in the processing of pro-hormones and neuropeptide precursors which are secreted in a regulated manner. PC1/3 and PC2 were shown to cleave neuroendocrine-specific proinsulin (Smeekens et al., Proc. Natl. Acad. Sci. USA, 89(18): 8822 (1992)), POMC (Benjannet et al., Proc. Natl. Acad. Sci. USA, 88(9): 3564 (1991)), pro-glucagon (Rouille et al., Proc. Natl. Acad. Sci. USA, 91(8): 3242 (1994)), pro-somatostatin (Xu and Shields, Biochimie 76: 257 (1994)), pro-neurotensin/neuromedin N (proNT/NN; Rovere et al., J. Biol. Chem., 271(19): 11368 (1996)) and pro-melanin concentrating hormone (MCH; Viale et al., J. Biol. Chem., 274(10): 6536 (1999)) C-terminally to KR or RR motifs (see Rouille et al., Front Neuroendocrinol. 16(4):322 (1995)). PC5A is also involved in the processing of proNT/NN and MCH (Barbero et al., J. Biol. Chem., 273(39): 25339 (1998)).